Project Summary/Abstract A novel technique for imaging biological tissue without labeling or staining, called Mueller matrix polarization microscopy, is introduced for visualizing the distribution of the anisotropic complex refractive index, an intrinsic property of the internal cellular and tissue microstructures. In addition to linear birefringence (the only polarization property currently investigated in microscopy) biological tissue (cells) exhibits also circular birefringence (optical activity in chiral media) and linear and circular dichroism (differential absorption for orthogonal polarizations) that can potentially be identified only from a complete Mueller matrix. Precise measurement of these properties will open a new window into the structural organization of complex biological entities. The new capabilities will provide fundamental insight into the microstructure of cells and living tissue, their transformations and interactions, studied in developmental and structural biology, leading to improved diagnosis, prognosis, and treatment of cancer and degenerative diseases. Physical Sciences Inc. (PSI) with consultation from Harvard University and the Center for System Biology, Massachusetts General Hospital will develop a simple yet versatile and robust polarization microscope for both reflection and transmission three-dimensional full Mueller matrix imaging, and to use this instrument for natural and synthetic tissue research. The polarization analysis is based on four liquid crystal variable retarders in a configuration designed without moving parts. The Mueller polarimeter is combined with stereoscopic imaging for three-dimensional reconstruction of the sample. The technology developed during this research will become a valuable tool with tremendous potential for biomedical imaging in general, and for imaging and monitoring cellular microstructures and their transformations in particular. Such a device may form the basis of a new assay with commercial applications to high- throughput imaging of zebrafish or other small animals used in drug discovery. PUBLIC HEALTH RELEVANCE: Project Narrative The purpose of this research is to develop a simple yet versatile and robust polarization microscope for three-dimensional polarization imaging, and to use this instrument for biological tissue analysis. This novel instrumentation will allow label-free, in-depth exploration of biological tissue structural properties leading to improved diagnosis and treatment of cancer and degenerative diseases.